Brain Disorder Due to Vitamin Deficiency Often Goes Unrecognized

Korsakoff syndrome — a neurocognitive disorder resulting from thiamine (vitamin B1) deficiency that often develops after untreated Wernicke encephalopathy — was difficult to diagnose and frequently led to death, a retrospective study showed.

Among 1,320 Korsakoff syndrome patients, 30.2% died over a median of 3.1 years, said Imelda Coffi, MD, of Assistance Publique-Hôpitaux de Paris in France, and co-authors.

Malnutrition (HR 1.54), alcoholic liver disease (HR 1.45), male sex (HR 1.45), and patient age between 80 and 89 years (HR 1.89) were associated with mortality, the researchers reported in JAMA Neurology.

In a well-documented subgroup of 114 patients, 61% had anterograde amnesia and 19% had a reported history of Wernicke encephalopathy. MRI abnormalities involving the Papez circuit and vascular leukoencephalopathy each were seen in 44.4% of this subgroup.

“This study emphasizes the substantial clinical burden of Korsakoff syndrome and the need for more standardized diagnostic approaches to facilitate earlier recognition and management of the disorder in both clinical practice and future research,” Coffi and colleagues wrote.

Korsakoff syndrome primarily affects episodic memory relative to other functions in patients who otherwise may seem alert. It typically emerges after undiagnosed or inadequately treated Wernicke encephalopathy, an acute condition caused by an insufficient supply of thiamine to the brain. Wernicke encephalopathy can be treated with high doses of intravenous thiamine.

Diagnosing Korsakoff syndrome is challenging due to a lack of consensus on diagnostic criteria, the researchers noted. Onset is often insidious, and diagnostic delays can range from months to years.

“Korsakoff syndrome has been extensively studied in patients with alcohol use disorder, given their high incidence of thiamine deficiency,” they observed. Thiamine deficiency can manifest in others with poor nutrition or eating disorders, they noted.

In a recent case report, Mass General Brigham physicians diagnosed a 62-year-old breast cancer patient with Wernicke-Korsakoff syndrome unrelated to alcohol use, likely due to malnutrition. Very rare cases of Wernicke encephalopathy also have been identified in patients prescribed semaglutide (Wegovy, Ozempic), with several people progressing to Korsakoff syndrome or death.

To better characterize Korsakoff syndrome, Coffi and colleagues evaluated electronic health records in the Clinical Data Warehouse of the Greater Paris University Hospitals of people with a Korsakoff diagnosis from 2017 through 2022. Mean age of Korsakoff syndrome patients was 62.9 years and 72.9% were men.

Based on ICD-10 codes, 43.7% of Korsakoff syndrome patients had alcohol use disorder and 17.9% were smokers. High blood pressure (22.1%) and alcoholic liver disease (15.7%) were common. Overall, 43.6% were admitted through the emergency department.

Because people diagnosed with Korsakoff syndrome had a significant amount of missing data, the researchers created a representative subgroup of 114 well-documented patients to better evaluate certain features.

In this subgroup, 95.6% of patients had Korsakoff syndrome due to alcohol use disorder. Less common causes included vascular dementia (17.5%), eating disorders (1.75%), brain tumor (1.75%), and gastrointestinal surgery complicated by malabsorption (0.8%).

Reasons for admission in the subgroup included cognitive impairment (36%), altered state of health (30.7%), and confusion (29%).

“Anterograde amnesia was the predominant memory impairment reported in the well-documented subgroup, underscoring the severity of memory impairment in Korsakoff syndrome and the challenges it may pose for timely diagnosis and clinical management,” Coffi and co-authors noted.

In the well-documented subgroup, only 22 people (19%) had a prior diagnosis of Wernicke encephalopathy, “supporting the hypothesis that Wernicke encephalopathy frequently goes unrecognized before the development of Korsakoff syndrome,” the researchers pointed out.

“Given that Wernicke encephalopathy and Korsakoff syndrome represent different clinical stages within the spectrum of thiamine deficiency-related brain injury, these results also raise the possibility that thiamine deficiency may have been underdiagnosed or inadequately treated in some patients,” they stated.

The study had several limitations, Coffi and colleagues acknowledged. A significant amount of data was missing from medical records: neuropsychological evaluation, brain MRI, and thiamine measurements were available for a minority of patients, they noted. In addition, some diagnoses may have been misclassified.

The high mortality in this study was consistent with previous research but “should be interpreted in the context of the comorbidities and the social vulnerabilities affecting these patients,” the researchers wrote.